Enteral compositions for the prevention and/or treatment of sepsis

ABSTRACT

The present invention relates to an enteral composition containing phospholipids, triglycerides and cholesterol or precursors thereof, which can be used in the treatment of sepsis. With the composition of the invention the natural level of chylomicrons is maintained, in particular in gut associated lymphoid tissue (GALT), which ensures that most of LPS and/or LTA which are released in the body can be neutralized, substantially decreasing the risk of locally occurring high levels of LPS and/or LTA and thus sepsis.

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to an enteral composition and usethereof containing phospholipids, triglycerides and cholesterol orprecursors thereof for the prevention and/or treatment of sepsis.

BACKGROUND OF THE INVENTION

[0002] Sepsis is a disorder which occurs when a relative large amount ofmicro-organisms or fragments thereof enters the body. It is alsoreferred to as endotoxemia or endotoxic shock. Endotoxin, orlipopolysaccharide (LPS) is a component of the outer cell membrane ofGram-negative bacteria. Lipoteichoic acid (LTA) is a component of theouter membrane of Gram-positive bacteria that can also give rise tosepsis. The intestines, especially the colon, are a reservoir of LPS andGram-negative bacteria, such as the common inhabitant Escherichia coli,but also of LTA and Gram-negative bacteria. LPS as well as LTA can enterthe systemic circulation by direct translocation from the gut or viatranslocation of Gram-negative and/or Gram-positive bacteria across theintestinal wall.

[0003] The presence of Gram-negative and/or positive bacteria and LPSand/or LTA in the gut is of no problem for a healthy person. However, inpersons or animals with imparted barrier function of the gut, forinstance caused by ischemia, surgery, chronic inflammation,radiotherapy, trauma, use of certain drugs, such as NSAID's orchemotherapeutics, critically ill persons such as persons underintensive supervision, or persons infected by invasive pathogens, LPS,LTA, Gram positive bacteria and/or Gram-negative bacteria can cross theintestinal wall and reach the circulation. Once these bacteria haveentered the system, LPS and/or LTA are released, which release is mainlydue to a high activity of the phagocytic system. This infection processcan also occur via the lungs (or during infections) or via peripheralbody parts (e.g. after traumata caused by accidents, or duringdecubitus, during the last phases of some pregnancy disorders (KLLPsyndrome) or during transfusions).

[0004] The release of LPS and/or LTA in the body can lead to an acutephase response and sepsis if LPS and/or LTA are not properlyneutralized. Such unproper neutralisation may occur in animals/personswith a compromised immune function, as is often the case aftermalnutrition, fasting, surgery, ischeamic conditions, severe burninjury, chronic infection, cancer therapy, imparted liver or spleenfunction, with critically ill persons, and also with persons that haveto recover directly after severe surgery.

[0005] The acute phase response can be determined by measuring levels ofC reactive protein in blood. C-reactive protein is an acute phaseprotein in man and an important component of the innate immune system.C-reactive protein activates the classical pathway of complement, whichis one of its main mechanisms in providing host defense. It has recentlybeen recognized that C-reactive protein interacts with the cells of theimmune system by binding to Fc gamma receptors. It may thus bridge thegap between innate and adaptive immunity and provide an early, effectiveantibacterial response. Furthermore, as it protects against the damaginginflammatory response to lipopolysaccharide and cytokines, it mayprevent the lethal side-effects of bacterial products. Risk of sepsiscan be determined by measuring in vivo protein synthesis in cells of theimmune system such as T lymphocytes as described in Januszliewicz et al.Clin. Nutr. 2001, 20(2), 181-182.

[0006] Sepsis can lead to multiple organ failure or death. It istherefore of great importance to find a method to treat, and especiallyprevent sepsis. Several approach have been proposed in the prior art toalleviate the symptoms or prevent or treat sepsis.

[0007] One approach has been given in WO 98/32428 which describes theuse of choline in an enteral feeding for the reduction and/or preventionof endotoxin induced injury and mortality. The amount administered is1.5 to 20 g per day. Choline is administered as choline tartrate.

[0008] Another approach has made use of phospholipids such as given inU.S. Pat. No. 5,434,183 which describes phospholipids containing ω-3fatty acids DHA and EPA in combination with vegetable oil and/or marineoil for anti-inflammatory and/or immunosuppressive effects in thetreatment of rheumatoid arthritis and sepsis. This enables the obtentionof a very low level of serum cholesterol and serum triglycerides.

[0009] WO 96/04916 describes protein and peptide free intravenousinjection preparations containing at least one phospholipid incombination with cholanoic acid or cholanoic acid salt for theprophylaxis and therapy of endotoxin related conditions. Optionally aneutral lipid can be added.

[0010] JP 05320043 describes a lipopolysaccharide scavenger consistingof phospholipids, in particular phosphatidyl choline, cholesterol andsaturated fatty acids, in particular myristic acid. These components areconverted into liposomes which are used in a solution for intravenousadministration for prevention or treatment of ischemia or tissueinjuries after ischemia. A suitable concentration ratio of cholesterolto phosphatidyl choline to myristic acid is 5-10:5-10:1-5.

[0011] U.S. Pat. No. 4,474,773 also describes the administration of thecombination of phospholipids, triglycerides, and cholesterol fortreating, among others, dysfunctions of the immune system, theadministration according to U.S. Pat. No. 4,474,773 being advantageouslymade intravenously.

[0012] The drawback of the compositions of the prior art for treatingsepsis is that the formulations are complex, e.g. a liposome. A furtherdrawback is that parenteral administration is intended which poses agreater risk to the patient. There is thus a need for a relativelysimple, effective, safe preparation for the prevention and treatment ofsepsis.

[0013] It has now been found that sepsis can be effectively preventedand/or treated by means of an enteral composition comprisingphospholipids, triglycerides and cholesterol or precursors thereof.

[0014] The present invention is based on the finding that LPS and/or LTAare detoxified in the circulation by incorporation into lipoproteinssuch as LDL (Low Density Lipoprotein), VLDL (Very Low DensityLipoprotein), chylomicrons and HDL (High Density Lipoprotein), inparticular chylomicrons. It is believed by the inventors thatchylomicrons play an important role in absorbing and transportinglipophilic substances in general such as food components and toxins(e.g. LPS and/or LTA), which can enter the body via the intestine butwhich can also be formed in case of elimination of remnants of deadbacterial cells in parts of the body. Chylomicrons are released in thegut associated lymphoid tissue (GALT) and take up LPS and/or LTA thatare released after lyses of bacteria in the enterocytes and inparticular in the lymph nodes. The chylomicrons are transported from thelymph nodes via the ductus thoracicus to the angulus venosus sinister,which transports the chylomicrons, and other lipoproteins, to the heart,which then transports them to the Reticulo Endothelial System (inparticular the spleen) and the liver (Kupffer cells). Chylomicrons canthus also be used as a vehicle for delivery in the liver of lipidsoluble substances, thereby preventing losses which can occur frommalabsorption.

[0015] Maintaining the natural level of chylomicrons, not only in bloodplasma, but especially in GALT e.g. over a relatively large part of thelength of the gut, ensures that most of the LPS and/or LTA which arereleased in several locations of the body e.g. in the lungs or gut, canbe neutralized, substantially decreasing the risk of locally occurringhigh levels of LPS and/or LTA.

[0016] In view of these findings, it is thus essential according to theinvention, contrary to the prior art, to administer the combination ofphospholipids, triglycerides, and cholesterol as an enteral compositionand not an intravenous composition. The combination of phospholipids,triglycerides and cholesterol is digested in the intestine ensuring arelatively constant release of chylomicrons for a prolonged period oftime in GALT since the product is relatively slowly digested. Further,the combination of phospholipids, triglycerides and cholesterol of theinvention has the advantage that the ingredients used need no specificpretreatments such as liposome formation which results in an effectiveproduct with a relatively low cost price. Further, enteraladministration of the composition is simple and safe.

[0017] Compared to U.S. Pat. No. 4,474, 773 which provides theintravenous administration of phospholipids, triglycerides andcholesterol, it has now been found, as above explained, that the enteraladministration favors the formation of chylomicrons in GALT, therebyproviding effective prevention and/or treatment of sepsis. In thisrespect, it is believed that the teaching of U.S. Pat. No. 4,474,773would be detrimental to such prevention and/or treatment. Indeed, U.S.Pat. No. 4,474,773 provides the stimulation of the immune system byincreasing the lymphocyte production. However, a problem encounteredwith this stimulation is that cytokines are in turn produced, whichlatter components are involved in the pro-inflammatory response thatunderlies sepsis (Intensive Care Med. 200;26 Suppl. 1:S124-8,Immunomodulatory therapy in sepsis, Kox W. J. et al.). This is furtherconfirmed by Inflamm. Res. 1998 May; 47(5):201-10, “The inflammatorybasis of trauma/shock associated multiple organ failure”, Yao Y. M. etal, which describes that activation of the immune system may produce ageneralized inflammation finally leading to sustained inflammation andmultiple organ damage. Accordingly, though following the teaching ofU.S. Pat. No. 4,474,773, a stimulation of the immune system would beprovided, this would nevertheless be detrimental to the treatment and/orprevention of sepsis.

[0018] Wang X. D. et al describe in Scand. J. Gastroenterol1994:1117-1121 that the enteric administration of phospholipidssignificantly reduced the incidence of bacterial translocation after 90%hepatectomy in rats. They describe that bacterial translocation undercertain conditions may cause sepsis or bacteremia. It is then concludedthat the decrease in bacterial translocation is probably the result ofphospholipids nourishing the intestinal mucosa and maintaining theintestinal barrier or by preventing of the barrier function as mucosalsurfactant. However, this article makes no mention of chylomicrons, letalone of its relation with the prevention or treatment of sepsis.

[0019] Still another approach has been given by WO 01/19356 whichprescribes the enteral administration of the combination of medium chaintriglycerides and lipid to prevent sepsis.

SUMMARY OF THE INVENTION

[0020] According to one aspect of the invention, there is provided theuse of phospholipids, triglycerides and cholesterol or precursorsthereof in the preparation of an enteral composition for the treatmentand/or prevention of sepsis.

[0021] According to another aspect of the invention, there is providedan enteral composition comprising phospholipids, triglycerides andcholesterol, wherein the composition comprises from 45% to 91% by weightof the composition of phospholipids.

[0022] According to a further aspect of the invention, there is providedan enteral composition comprising phospholipids, triglycerides andcholesterol, wherein the cholesterol is present within the compositionin an amount of from 0.5% to 3% by weight of the composition.

DETAILED DESCRIPTION OF THE INVENTION

[0023] An essential element of the present invention is a phospholipid.Phospholipids for use herein are selected from phosphatidyl choline,phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl serine,phosphatidyl glycerol, phosphatidic acid, and mixtures thereof.

[0024] Preferably, the phospholipids are administered as a mixture ofphospholipids, in particular comprising phosphatidyl choline and one ormore of phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidylserine, phosphatidyl glycerol, and phosphatidic acid. More preferably,the composition contains at least phosphatidyl choline and phosphatidylethanolamine.

[0025] Typically, phospholipids for the purpose of the present inventionwill be present in an amount of from 45% to 91% by weight of thecomposition. Still, it has now also been found that the presence of ahigh level of phospholipids in the invention composition furtherincreased the formation of chylomicrons, and thus further improved theprevention and/or treatment of sepsis. Accordingly, it is preferred whenphospholipid is present in high amount that a level of from 48% to 78%,more preferably of 55% to 69 wt % of phospholipids is used or present inthe invention composition. However, when triglycerides is desired aspredominant component, the level of phospholipids within the compositionis then preferably of from 10 to 45% by weight of the composition.

[0026] As a source of phospholipids, preparations enriched in aparticular phospholipids or containing relatively pure (synthetic)phospholipids can be used. Though after consumption of syntheticphospholipids and even lysophospholipids chylomicrons are formed invivo, it is preferred to use natural sources, in particular egg and soylecithin. Indeed, these are more economical, are favored by consumersbut also can sometimes be more stable. The following natural sources ofphospholipids have been found very suitable:

[0027] A preferred soy lecithin for use herein contains, based on totalphospholipid content, 35 to 50 wt. % phosphatidyl choline and 25 to 40wt. % phosphatidyl ethanolamine.

[0028] A preferred egg phospholipid extract for use herein comprises 50to 70 wt % phosphatidyl choline and 15 to 22 wt % phosphatidylethanolamine.

[0029] The fatty acids in the phospholipids in particular comprise lessthan 30% docosahexaenoic and/or eicosapentaenoic acid.

[0030] Phospholipids are administered in an amount of 0.01 to 1.5 gramper kilogram body weight per dose. For humans this results in about 0.6to 80 g per dose. As described above doses are administered at leastonce every 24 hours, but preferably every 2-12, more preferably every3-8 hours or even on a continuous basis.

[0031] The daily dose of phospholipids is chosen in such a way that itresults in either restoring the lipoproteins from low levels to levelsobserved in healthy well fed persons or even enhancing the levels in ashort period of time to 120 % or even above 150 %, compared to a healthyperson and/or to enhance the phospholipid/lipoprotein ratio in theblood. Indeed, it has been found that it is preferred to have aweight/molar ratio which is high in favor of the phospholipids.Chylomicrons (and other lipoproteins) containing a high amount ofphospholipids will have a higher capacity in neutralising endotoxin.Furthermore, a high amount of phospholipids will aid in absorption oftriglycerides and also improve the gastrointestinal barrier function.

[0032] In particular, the phospholipid dosage is preferably specific tothe type of patient as well as to the type of administration. Thus,three groups of patients can be defined:

[0033] Group 1, which are patients who can be fed with enteral nutritionand who consumes triglycerides and cholesterol on a regular basis;

[0034] Group 2, which are malnourished patients or with impartedmetabolic capacity in the enterocytes;

[0035] Group 3, which are extremely weak patients typically fed byparenteral ways.

[0036] Patients from Group 1 and 2 would benefit from the various typesof nutrition. However, it has been found that when long term tubefeeding is used, it is preferred to use the invention composition whichis predominant in triglycerides (i.e. more than 50% by weight) becausethe lipids that are present in the gut are provided from the compositionadministration. Accordingly, for a complete enteral nutritioncomposition and considering a consumption of 2000 kcal a daily dosage ofphospholipids for long term tube feeding is preferably of from 4-30 g,more preferably 6-28 g.

[0037] When short term tube feeding is used, it is preferred to use theinvention composition which is predominant in phospholipids as residualtriglycerides can still be present in the gut provided from earliermeals and as the cholesterol synthesis in enterocytes would then not bestrongly imparted. Accordingly, for a complete enteral nutritioncomposition and considering a consumption of 2000 kcal, a daily dosageof phospholipids for long term tube feeding is preferably of from 20-75g, more preferably 28-60 g.

[0038] When a supplement is used, it has been found that group 1 and 2,although to a less extent for group 2, would benefit from a supplementthat is predominant in phospholipids (i.e. above 45% by weight) as thiswould enable group 1 patients to consume a regular diet of triglyceridesand cholesterol whereas for group 2 patients, this would enable them toconsume the essential elements to their organism. Accordingly, for asupplement composition predominant in phospholipids and considering aconsumption of 200-600 ml and a lipid content of about 5%, a dailydosage of phospholipids for a supplement is preferably of from 5-28 g,more preferably 15-25 g, whereas for a supplement compositionpredominant in triglycerides, a daily dosage of phospholipids for asupplement is preferably of from 1-13 g, more preferably 2-8 g.

[0039] It was further found that supplement on group 3 patients would bebeneficial by administering small quantities (50-400 ml) of theinvention composition predominant in triglycerides.

[0040] Another essential element of the present invention is atriglyceride. Triglycerides of the invention are in particular selectedfrom glycerol esterified with long chain fatty acids. With long chainfatty acids, fatty acids are meant with at least 18 carbon atoms. Theamount of long chain fatty acids related to the total amount of fattyacids in the triglyceride, should be at least 50% and preferably morethan 60% in order to observe significant chylomicron formation in vivo.Preferred long chain fatty acids are stearidonic, oleic, α-linolenic,linoleic, gamma-linolenic, conjugated linoleic acid, docosahexaenoic,eicosapentaenoic and arachidonic acid. More preferably, polyunsaturatedfatty acids are used which result in more efficient chylomicrons, i.e.in chylomicrons which are more suitable to scavenge LPS and/or LTA. Theamount of myristic acid in the triglyceride fraction is preferablysmaller than 40%, more preferably smaller than 25 wt. %.

[0041] Examples of triglycerides are vegetable oils such as soy oil,corn oil, olive oil, sunflower oil, sesame oil, safflower oil, wheatgerm oil, arachidic oil, evening primrose oil, egg oil, or mixturesthereof, but also marine oils, such as fish oil and algal oil aresuitable, optionally mixed with one or more vegetable oils.

[0042] Typically, triglycerides for the purpose of the present inventionwill be present in the mixture of triglycerides, cholesterol andphospholipids in an amount of at least 7% to less than 80 wt. %. Still,it is preferred when phospholipid is present in high amount that a levelof from 7% to 50 wt % of triglycerides is used or present in theinvention composition. However, when triglycerides is desired aspredominant component, the level of triglycerides within the compositionis then preferably of more than 50 to 80% by weight of the composition.

[0043] The dose of triglycerides is 0.01 to 1 g/kg body weight. Thisresults in administration of about 0.6 to 60 g triglycerides per dose todiseased humans.

[0044] Still another essential element of the present invention ischolesterol or its precursor thereof Indeed, the presence of cholesterolin addition to the presence of phospholipids and triglycerides has beenfound beneficial to the combination in the sense that more chylomicronswere produced than with the only combination of phospholipids andtriglycerides, thus in turn providing better prevention and/or treatmentof sepsis.

[0045] In particular one or more of cholesterol or cholesteryl esterslike those that occur in natural extracts (egg) and synthetic sourceslike esters with organic acids, e.g. cholesteryl acetate, hemisuccinate,n-butyrate, oleate, or with phospholipids are used. Preferably, acholesterol-rich fraction isolated from egg is used.

[0046] Typically, cholesterol or equivalents thereof for the purpose ofthe present invention will be present in the mixture of triglycerides,cholesterol and phospholipids in an amount of from 0.5% to 8% by weightof the composition. Still, it has also been found that when cholesterolwas present within the specific range of from 0.5 wt. % to 3 wt. %,preferably 0.7 to 1.5%, the best response in terms of stability of thecomposition, especially when soy lecithin is used, and production ofchylomicrons was obtained. Invention composition comprising eggcholesterol and egg lecithin have sometimes a tendency to an undesiredcreaming of the composition. Use of such specific cholesterol levelcombined with soy derived phospholipids has been found to provide aremedy to this problem.

[0047] The dose of this ingredient, calculated as cholesterol ispreferably 2 mg to 120 mg per kg body weight per dose, preferably offrom 14 mg to 80 mg per kg body weight per dose, resulting in a dose of0.1 to 7 g in humans, preferably of from 1 to 5.5 g per dose.

[0048] The components of the composition of the invention (cholesterol,phospholipids and triglycerides) are present in their natural form or asseparate ingredients. This means that liposomes are not envisaged by theinvention.

[0049] In the preparation of the invention the weight ratio ofcholesterol to phospholipids to triglycerides is preferably 1:3-80:3-90,more preferably 1:3-20:3-90, more preferably 1:6-16:6-60, mostpreferably is 1:6-12:12-40.

[0050] Still, as described hereinbefore, it is preferred for the purposeof the invention when a high amount of phospholipids is presentresulting in a weight ratio of cholesterol to phospholipids totriglycerides of 1:20-80:3:80, more preferably of 1:20-75:20:75.

[0051] As a source for the combination of phospholipids, cholesterol andtriglycerides of the invention eggs such as egg in the form of egg oilor egg powder can also be used. Eggs, in particular the lipid fractionthereof; already contain the desired components. Depending on the enduse of the composition and the type of lipid extract that is used, allor some of the components (cholesterol, phospholipids and triglycerides)need to be supplemented to fall within the ranges indicated, such thatthe diet of the patients contains the right amounts of these components.It is particular advantageous if eggs are used of animals having aspecific lipid mixture in their feed, which eggs have an increasedcontent of α-linolenic acid, conjugated linoleic acid anddocosahexaenoic acid.

[0052] Besides that it contains the suitable components of theinvention, eggs also have the advantage that they contain beneficialproteins. The protein fraction of eggs contains immunoglobulins whichcan interact with bacteria. The presence of immunoglobulins, inparticular IgY, together with the components of the invention in theintestine, provides a very efficient system which prevents that bacteriatranslocate through the intestinal wall.

[0053] It is preferred that these immunoglobulins, in particular IgY,have been made suitable to bind to specifically those bacterial strainswhich form the greatest risk for causing sepsis. Such immunoglobulinscan be induced in birds and transferred to eggs according to methodsknown in the art. A particular suitable product to be used according tothe invention is thus hyperimmunized egg, which can be used as suchafter a light pasteurization, which keeps the immunoglobulinspredominantly in undenatured and active state.

[0054] The composition preferably contains at least 0.02 g, preferably0.08 to 1.6 g, more preferably 0.08 g to 0.9 g proteins per dose per kgbody weight.

[0055] When proteins are used that originate from eggs of hyperimmunizedbirds, the daily dose of IgY that can be administered is then preferablyof from 0.2 to 120 mg. Still, as the effectivity of the IgY whencombined with invention composition has been found to improve theprevention of the bacteria translocation, the daily dose of IgY that canbe administered is more preferably within the range of from 0.2 to 800mg, most preferably of from 10 to 600 mg. The dose of this ingredient ispreferably 0.1 mg to 10 mg per kg body weight per dose.

[0056] The doses for the treatment of the human/animal as described inthe present application are given as dose per kg body weight. The amountfor a dose can thus be determined based on the weight of the subject tobe treated. The daily doses can be calculated by multiplying the dosewith the number of times that the dose is consumed per day. The doseregime should be adjusted to maintain a high level of chylomicrons inthe lymph e.g. by repeating dosing every 2-12 hours, preferably 3-8hours or even on a continuous basis. For a group of patients tubefeeding in the gut is recommended.

[0057] The enteral composition can further contain lactic acid bacteria,products of lactic acid bacteria, prebiotics, extra L-glutamine and/orL-arginine, fibres, carbohydrates, polysaccharides, vitamins, mineralssuch as zinc which will promote the adsorption of lipid-solublesubstances, and other components as normally present in an enteralfeeding.

[0058] In particular the composition contains fat soluble substances.These are in particular selected from vitamin K (menaquinones),ubiquinones, carotenoids such as vitamin A, specific fatty acids such asconjugated linoleic acid, lipoic acid and vitamin D. Inclusion of one ormore of these components in the lipid mixture of the inventioneffectively decreases the prevalence of sepsis, decreases acute phaseresponse and improves recovery after surgery or trauma

[0059] When they are included in an enteral product together with thelipid mixture of the invention and optionally with zinc salt, loweramounts of these fat soluble substances than those in the prior art canbe effective.

[0060] It is also preferred to incorporate berberin or extracts ofBerberis aristata or Coccinia fenestratum in the preparation in anamount of 10-100, preferably 20-50 mg/kg body weight per dose.

[0061] The enteral composition of the invention is preferably used inthe prevention and/or treatment of sepsis, bacteremia and/orendotoxaemia (endotoxic shock) and to delay acute phase response. Inparticular the composition is used for treatment of patients undergoingmajor surgery, critically ill patients, patients with Inflammatory Boweldisease (IBD), patients with HELLP syndromes, patients with an enhancedrisk for bacterial translocation and sepsis in general, in particularthose suffering from major trauma, burns, pneumonia, especially causedor complicated by bacteria., decubitus, during radio/chemo therapy orhaving a compromised immune system such as premature infants or elderlydiseases.

[0062] In case of surgery, it is believed that the risk of endotoxaemiais related to the fact that patients need to fast preoperatively andthat after surgery take only little food. As a result, the normal amountof chyloricrons is diminished, which makes them more vulnerable fordamage caused by LPS. Generally these patients can take the compositionof the invention until about 3 hours before surgery and shortly aftersurgery, but also the option of taking the composition during a shorterperiod before surgery is envisaged by the invention. In this case thetotal lipid level in the composition will typically be in the range of 5to 70, preferably 15 to 50 g per dose. This dose can be supplied bymeans of a supplement for oral use, preferably a liquid in a relativelylow volume, for example 100 to 700, preferably 150 to 600 ml.

[0063] The composition can also be taken by persons that allow intake ofa restricted volume, such as persons suffering from anorexia nervosa orpersons in the end stages of diseases such as cancer or AIDS, but alsomany elderly people. In this case the triglyceride level in thecomposition will be in the range of 0.7 to 30, preferably 2 to 15g/dose, administered in a relatively low volume.

[0064] Mammals in general which are susceptible to infections, such asdue to irregular feed regimes, e.g. cows and pigs, in particular weaningpigs, which can result in lower meat quality, can also be treated withthe composition of the invention. Stress during transport can alsoresult in bacterial translocation in animals.

[0065] The enteral composition of the present invention can be an oralor tube feeding, preferably a tube feeding. The oral feeding can be acomplete feeding or a feed supplement, in liquid form or as a capsule orpowder. Preferred liquid forms are dispersions. Intravenous compositionsfor the reasons explained hereinbefore are excluded from the invention.

[0066] Thus the invention also provides an enteral feed containing(dose)

[0067] 8-120 g, preferably 12-80 g of the combination of cholesterol,phospholipids and triglycerides

[0068] 5-100 g, preferably 12-60 g of a protein fraction and

[0069] 1.2-400 g, preferably 5-200 g of a carbohydrate fraction.

[0070] Examples of enteral feedings are feedings that can beadministered via a tube to a patient, for instance undergoingcardiosurgery, containing 0.5% to 7%(w/v), preferably 3 to 6% %(w/v)phospholipids in the presence of proteins, fat, sugars, fibrous andother components which are normally present in a complete enteralfeeding. The feeding is started 24 hours before the surgery, whichdepending on the condition of the patient can be either by sip-feedingor tube-feeding, and is continued during 24 to 72 hours after thesurgery via tube. Tube-feeding can also be carried out directly into theduodenum, thereby advantageously maintaining an empty stomach andpreventing aspiration during surgery. Continuous treatment with theinvention composition is an important and preferred aspect of thepresent invention. Indeed, continuous treatment, i.e. starting beforeoperation, if any, and continuing for 4 to 5 days, provides a sustainedproduction of chylomicrons, thereby providing a better and long lastingresistance against microbial infections, in particular those giving riseto sepsis.

[0071] A capsule or powdered food supplement containing the lipidmixture according to the invention is given to people with inflammatorybowel disease. The supplement may further contain fibers,oligosaccharides, vitamins, in particular fat soluble vitamins, asindicated above, probiotics, anti-oxidants, herbal or plant extracts,proteins or peptides, etc. The supplement is given to patients inremission in order to prevent recurrence of inflammation or to alleviatethe inflammation once it re-occurs.

[0072] A liquid sip feeding with a phospholipid (why only phospholipids)concentration of 1 -5% (w/v) can for instance be administered to apatient with obstructive jaundice, who will undergo surgery. In thefeeding proteins, fats, polysaccharides and micronutrients may bepresent. The feeding is administered 24-12 hours before surgery andcontinues as soon as possible after surgery for 24 to 72 hours.

[0073] The composition of the invention is also suitable for newborn andpremature children or animals.

[0074] The following are non-limiting examples illustrating the presentinvention:

EXAMPLE 1

[0075] Complete feeding containing per 100 ml: Energy 125 kcal Protein  6 g (3 g egg white protein, 3 g whole milk protein) N-acetyl cystein0.04 g lipids  4.5 g including: phospholipids 1.2 g triglycerides 3.1 gcholesterol 0.2 g Carbohydrates 15.5 g Fiber  0.2 g

[0076] minerals, trace elements and vitamins as known in the art vitaminK  30 μg coenzyme Q10   5 mg tocopherols   1 mg αTE carotenoids 0.1 mg

EXAMPLE 2

[0077] Liquid feeding to be used as a supplement containing per 100 mlEnergy 100 kcal protein   9 g lipids  2.1 g including: phospholipids 0.9 g vegetable oil 1.05 g (sesame oil and olive oil (1:3)) cholesterol0.36 g carbohydrates 11.4 g

[0078] minerals, trace elements, vitamins and other components as knownin the art, for instance Na, K, Cl, Ca, Mg, Fe, Cu, P, Zn, I, vit. A, D,C, E, B1, B2, B6, B12, folic acid, pantothenic acid, niacine, biotine.

EXAMPLE 3

[0079] Tube feeding containing per 100 ml Protein (casein)  4.0 gCarbohydrates 12.3 g Fat  3.9 g comprising 1 g phospholipid, 2.9 gtriglycerides and 32 mg cholesterol

[0080] amounts according to the general guidelines on food for vitamins,minerals, choline, and trace elements are included

EXAMPLE 4

[0081] Egg Preparation

[0082] Hens are made hyperimmune by injecting them, when they are stillpullets, one or more times with an extract of human pathogens that areknown to play a role in sepsis. Eggs are collected and the wholecontents are manufactured as described in the prior art in order toobtain a pasteurized and spray dried product that is rich inimmunoglobulins against these pathogens, in particular IgY. A suitablemethod can be found in U.S. Pat. No. 5,585,098.

EXAMPLE 5

[0083] The liquid egg according to example 4 could also be extracted inorder to obtain the lipid fraction and an IgY enriched fraction using amethod as described in Juneja L. R., Egg Yolk lipids, CRC Press 1997,0-8493-4005, page 73-98.

EXAMPLE 6

[0084] A liquid product is manufactured that comprises per 400 ml

[0085] 16 g whole milk protein

[0086] 8 g safflower oil

[0087] 2 g corn oil

[0088] 1 g deodorized fish oil

[0089] 8 g lecithin

[0090] 1 g cholesterol (5% wt on mixt lipid)

[0091] 30 g maltodextrines

[0092] amounts according to the general guidelines on food for vitamins,minerals and trace elements are included

EXAMPLE 7

[0093] Preparation for Surgery Patients

[0094] A liquid preparation is manufactured that comprises per 400 ml

[0095] 20 g egg white protein

[0096] 24 g egg oil

[0097] 25 g maltodextrines

[0098] 800 μg folic acid

[0099] 100 μg vitamin B12

[0100] 3 mg pyridoxine

[0101] 40 mg zinc sulphate

[0102] amounts according to the general guidelines on food for vitamins,minerals and trace elements are included

EXAMPLE 8

[0103] Nutritional Supplement for Cancer Patients

[0104] Bar used as snack having a salty and herb taste

[0105] Per 25 g the bar comprises

[0106] 6 g egg lipids comprising per 100 g fatty acids >0.5 g DHAand >1.7 g AA, 400 μg folic acid

[0107] 5 μg cyanobalamin

[0108] 2 mg pyridoxin

[0109] 2 g egg protein

[0110] 200 μm magnesium carbonate

[0111] 15 mg zinc oxide

[0112] 100 mg calcium sulphate

[0113] About 2 g additives to give a salty or herb taste.

[0114] Make up with glucose syrup to 25 g and manufacture the bar asknown in the art.

EXAMPLE 9

[0115] Formula for premature infants containing per 100 ml ready to useformula prepared according to methods known in the art:

[0116] 1.2% protein of whole milk

[0117] 3.0% of a fraction consisting of

[0118] 78% of a mixture of vegetable oils

[0119] 20% soy phospholipids

[0120] 2% cholesterol

[0121] 8% carbohydrates including lactose

[0122] 80 μg RE Vitamin A

[0123] 20 μg Vitamin K

EXAMPLE 10

[0124] Preparation for Persons that Suffer from Severe Diarrhea

[0125] Bar used as snack having a salty and herb taste

[0126] Per 25 g the bar comprises

[0127] 8 g whole egg powder

[0128] 400 μg folic acid

[0129] 5 μg cyanobalamin

[0130] 2 mg pyridoxin

[0131] 200 μm magnesium carbonate

[0132] 15 mg zinc oxide

[0133] 100 mg calcium sulphate

[0134] 0.2 mg vitamin K

[0135] 0.2 mg RE vitamin A

[0136] About 2 g additives to give a salty or herb taste.

[0137] Make up with glucose syrup to 25 g and manufacture the bar asknown in the art.

EXAMPLE 11

[0138] Tube feeding containing per 100 ml Protein  7.5 g Carbohydrates14.5 g Fat 4.17 g comprising 1 g phospholipids and 21 mg cholesterol

[0139] amounts according to the general guidelines on food for vitamins,minerals, choline, and trace elements are included.

1-25. (cancelled)
 26. A method for the treatment and/or prevention ofsepsis, endotoxemia and/or bacteremia, which method comprisesadministering to a human or an animal in need thereof an enteralcomposition comprising phospholipds, triglycerides and cholesterol orprecursors thereof.
 27. The method according to claim 26, wherein thephospholipids are administered in a dose of 1 to 75 gram per day. 28.The method according to claim 26, wherein the triglycerides areadministered in a dose of 0.6 to 60 gram per day.
 29. The methodaccording to claim 26, wherein cholesterol or precursors thereof areadministered in a dose of 0.1 to 7 gram per day.
 30. The methodaccording to claim 26, where sepsis, endotoxemia and/or bacteremia isassociated with major surgery, critical illness, Inflammatory BowelDisease (IBD), HELLP syndrome, an enhanced risk for bacterialtranslocation, in particular major trauma, burns, pneumonia, especiallycaused or complicated by bacteria, decubitus, during radio/chemotherapyor with a compromised immune system.
 31. The method according to claim26, wherein the composition is administered to persons that do not allowintake of large volume, in particular to patients suffering fromanorexia nervosa, cancer or to AIDS patients and elderly.
 32. The methodaccording to claim 26, wherein the composition is administered toneonates.
 33. The method according to claim 26, wherein the compositionis administered to farm animals or weaning pigs before they areslaughtered.
 34. An enteral composition comprising phospholipids,triglycerides and cholesterol or precursors thereof, suitable for thetreatment and/or prevention of sepsis, endotoxemia and/or bacteremia,wherein the composition comprises from 45% to 91% by weight of thecomposition of phospholipids, from 0.5% to 8% by weight of thecomposition of cholesterol, and wherein the weight ratio of cholesterolto phospholipids to triglycerides is 1:3-80:3-90.
 35. The compositionaccording to claim 34, wherein the cholesterol is present in an amountof from 0.5% to 3% by weight of the composition.
 36. The compositionaccording to claim 34, wherein the phopholipids are in the form of amixture of phospholipids comprising phosphatidylcholine and one or moreof phosphatidylethanolamine, phosphatidylinositol, phosphatidyl serine,phosphatidyl glycerol, and phosphatidic acid.
 37. The compositionaccording to claim 34, wherein the triglycerides contain at least 50 wt.% long chain fatty acids with at least 18 carbon atoms, in particularlong chain polyunsaturated fatty acids with at least 18 carbon atoms.38. The composition according to claim 34, wherein the triglycerides areselected from vegetable oils, marine oils, and mixtures thereof,selected from soy oil, corn oil, olive oil, sunflower oil, sesame oil,safflower oil, wheat germ oil, arachidic oil, evening primrose oil, eggoil, fish oil, algal oil and mixtures thereof.
 39. The compositionaccording to claim 34, wherein cholesterol and precursors thereof areselected from cholesterol and cholesterylesters and/or salts thereof.40. The composition according to claim 34, wherein the weight ratiocholesterol to phospholipids to triglycerides is 1:3-20:3-90.
 41. Thecomposition according to claim 40, wherein the weight ratio cholesterolto phospholipids to triglycerides is 1:6-16:6-60.
 42. The compositionaccording to claim 34, wherein the weight ratio cholesterol tophospholipids to triglycerides is preferably 1:20-80:3-80.
 43. Thecomposition according to claim 42, wherein the weight ratio cholesterolto phospholipids to triglycerides is 1:20-75:20-75.
 44. The compositionaccording to claim 34, wherein the composition contains egg or an eggfraction.
 45. The composition according to claim 34, wherein thecomposition further contains immunoglobulins.
 46. The compositionaccording to claim 34, wherein the composition contains soy lecithin.47. The composition according to claim 34, wherein the composition is anoral feeding, tube feeding or infant formula.
 48. The compositionaccording to claim 34, wherein the composition further contains proteinsor peptides.
 49. The composition according to claim 34, wherein thecomposition further contains one or more fat soluble substances,selected from vitamin K (menaquinones), ubiquinones, carotenoids such asvitamin A, specific fatty acids such as conjugated linoleic acid, lipoicacid, vitamin D and mixtures thereof.
 50. A unit enteral feedingcomposition, suitable for the treatment and/or prevention of sepsis,endotoxemia and/or bacteremia, containing 8-120 g of the combination ofcholesterol, phospholipids and triglycerides, wherein the weight ratioof cholesterol to phospholipids to triglycerides is 1:3-80:3-90; 5-100 gof a protein fraction; and 1.2-400 g of a carbohydrate fraction.
 51. Thecomposition according to claim 50, wherein tile phospholipids are in theform of a mixture of phospholipids comprising phosphatidylcholine andone or more of phosphatidylethanolamine, phosphatidylinositol,phosphatidyl serine, phosphatidyl glycerol, and phosphatidic acid. 52.The composition according to claim 50, wherein the triglycerides containat least 50 wt. % long chain polyunsaturated fatty acids with at least18 carbon atoms.
 53. The composition according to claim 50, wherein thetriglycerides are selected from vegetable oils, marine oils, andmixtures thereof, selected from soy oil, corn oil, olive oil, sunfloweroil, sesame oil, safflower oil, wheat germ oil, arachidic oil, eveningprimrose oil, egg oil, fish oil, algal oil and mixtures thereof.
 54. Thecomposition according to claim 50, wherein cholesterol and precursorsthereof are selected from cholesterol and cholesterylesters and/or saltsthereof.
 55. The composition according to claim 50, wherein the weightratio cholesterol to phospholipids to triglycerides is 1:3-20:3-90. 56.The composition according to claim 55, wherein the weight ratiocholesterol to phospholipids to triglycerides is 1:6-16:6-60.
 57. Thecomposition according to claim 50, wherein the weight ratio cholesterolto phospholipids to triglycerides is preferably 1:20-80:3-80.
 58. Thecomposition according to claim 57, wherein the weight ratio cholesterolto phospholipids to triglycerides is 1:20-75:20-75.
 59. The compositionaccording to claim 50, wherein the composition contains egg or an eggfraction.
 60. The composition according to claim 50, wherein thecomposition further contains immunoglobulins.
 61. The compositionaccording to claim 50, wherein the composition contains soy lecithin.62. The composition according to claim 50, wherein the composition is anoral feeding, tube feeding or infant formula.
 63. The compositionaccording to claim 50, wherein the composition further contains one ormore fat soluble substances, selected from vitamin K (menaquinones),ubiquinones, carotenoids such as vitamin A, specific fatty acids such asconjugated linoleic acid, lipoic acid, vitamin D and mixtures thereof.